Recovery from acute hypoxia: A systematic review of cognitive and physiological responses during the ‘hypoxia hangover’

Recovery of cognitive and physiological responses following a hypoxic exposure may not be considered in various operational and research settings. Understanding recovery profiles and influential factors can guide post-hypoxia restrictions to reduce the risk of further cognitive and physiological deterioration, and the potential for incidents and accidents. We systematically evaluated the available evidence on recovery of cognitive and basic physiological responses following an acute hypoxic exposure to improve understanding of the performance and safety implications, and to inform post-hypoxia restrictions. This systematic review summarises 30 studies that document the recovery of either a cognitive or physiological index from an acute hypoxic exposure. Titles and abstracts from PubMed (MEDLINE) and Scopus were searched from inception to July 2022, of which 22 full text articles were considered eligible. An additional 8 articles from other sources were identified and also considered eligible. The overall quality of evidence was moderate (average Rosendal score, 58%) and there was a large range of hypoxic exposures. Heart rate, peripheral blood haemoglobin-oxygen saturation and heart rate variability typically normalised within seconds-to-minutes following return to normoxia or hyperoxia. Whereas, cognitive performance, blood pressure, cerebral tissue oxygenation, ventilation and electroencephalogram indices could persist for minutes-to-hours following a hypoxic exposure, and one study suggested regional cerebral tissue oxygenation requires up to 24 hours to recover. Full recovery of most cognitive and physiological indices, however, appear much sooner and typically within ~2–4 hours. Based on these findings, there is evidence to support a ‘hypoxia hangover’ and a need to implement restrictions following acute hypoxic exposures. The severity and duration of these restrictions is unclear but should consider the population, subsequent requirement for safety-critical tasks and hypoxic exposure.


Introduction
Hypoxia is a state of insufficient oxygen which can compromise normal physiological and cognitive functions, and manifests when breathing air with a lower partial pressure of oxygen (PO 2 ) compared to sea-level (i.e. <159 mmHg) [1,2]. The initial compensatory responses to the resulting hypoxaemia (i.e. low arterial partial pressure of oxygen) include cardiopulmonary, respiratory and metabolic, which aim to maintain oxygen supply to vital tissues, but tissues eventually desaturate when PO 2 is sufficiently low. The brain's high rates of oxidative metabolism (20-25% resting metabolic rate) make it vulnerable to oxygen depletion [3] and energetically-demanding cognitive functions are easily impaired during hypoxic exposures [1,4]. Temporal recovery from hypoxia is assumed to be rapid since peripheral blood haemoglobin reoxygenates within seconds-to-minutes; however, cognitive and physiological perturbations can persist beyond the recovery of blood and tissue oxygenation [5]; a state that has been colloquially termed the 'hypoxia hangover' [6].
The recovery profiles of cognitive and physiological responses from an acute hypoxic exposure have performance and safety implications for various operational and research populations. For example, military aviators undertake hypoxia recognition training at least once every five years and are prohibited from flying duties for the following 12-24 hours. Recent studies by the Naval Medical Research Unit (Dayton, Ohio, USA), however, have demonstrated cognitive and physiological indices fully recover almost immediately [7] or within 2-4 hours [5] following a hypoxic exposure, which suggests the grounding period for military aviators could be reduced. If post-hypoxia restrictions are implemented, the influence of the hypoxic dose (barometric pressure, fraction of inspired oxygen [F I O 2 ] and duration of exposure), recovery procedures (e.g. normoxic or hyperoxic breathing) and safety-critical nature of subsequent tasks should also be considered. There is a need to evaluate if post-hypoxia restrictions are required for different populations and to establish clear evidence-based recommendations that inform operational, training and research scenarios.
Therefore, we conducted a systematic review examining the recovery profiles of cognitive and physiological responses following an acute hypoxic exposure in healthy individuals. The aim was to determine whether post-hypoxia restrictions should be implemented, evaluate if the hypoxic dose or recovery procedures influence cognitive and basic physiological indices, and identify gaps in knowledge for future investigations. Outcomes will be crucial for populations that experience hypoxia during training or operational duty (e.g. military aviators), and to manage participants of research studies evaluating the effects of hypoxic interventions.

Methodology
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines [8]. This review was not preregistered as it stemmed from a project to inform recommendations following normobaric and hypobaric hypoxia recognition training of military aviators within the Royal New Zealand Air Force.

Search
We searched titles and abstracts from PubMed (MEDLINE) and Scopus from inception to July 2022 for potential research studies using the search terms and Boolean operators: (hypoxia or hypoxic) AND (hangover OR recovery) AND (cognition OR cognitive OR "cognitive performance" OR "flight performance" OR mood OR sleepiness OR symptoms OR effort OR physiology OR physiological OR oxygenation OR "oxygen saturation" OR "heart rate" OR "heart rate variability" OR "blood pressure" OR ventilation OR "respiratory rate" OR respiration OR "blood gases") NOT (animal OR murine OR rodent OR mice OR porcine OR dog OR fish OR cell). Furthermore, additional articles known to the first author (DMS) that were not identified in the literature search were added and titles (only) of the following were screened by DMS: 1) reference lists of eligible articles; 2) forward citation tracking using Google Scholar of eligible articles; and 3) searching key journals and Google Scholar using a combination of the terms: hypoxia, hypoxic, recovery and hangover. All potential articles identified through other sources were screened by DMS immediately following retrieval. Full details of the screening process are displayed in Fig 1.

Inclusion and exclusion criteria
We included studies fulfilling the following criteria: 1) between-or within-subject experimental trials; 2) human participants of any age with no known medical conditions; 3) an objective measure of cognition or physiology during recovery from an acute hypoxic exposure; and 4) peer reviewed full text original research studies published in English. Acute hypoxia was defined as <300 min of breathing hypoxic air that lowered peripheral blood haemoglobin-oxygen saturation (SpO 2 ) to <90% (i.e. normobaric or hypobaric hypoxia) and recovery was defined as the period of breathing air that increased and normalised peripheral blood SpO 2 to >95% following an acute hypoxic exposure. We excluded studies if: 1) the control or baseline group (or condition) were not administered air able to maintain SpO 2 >95%; 2) other interventions known to effect cognition were included in conjunction with oxygen manipulation, except for carbon dioxide; 3) single or accumulated repeated hypoxia exposures were administered beyond 300 min; 4) hypoxia was repeatedly interrupted by normoxic breathing; and 5) cognitive and/or physiological data were not adequately reported. As we were specifically interested in physiological responses that can be readily measured in military aviation training and operational settings, we restricted our physiological indices of interest to ventilatory, cardiovascular, regional cerebral tissue haemoglobin-oxygen saturation (rSO 2 ), SpO 2 , and cardiac autonomic responses. Measures of less interest and low feasibility in the training and operational setting (e.g. intra-ocular pressure, limb blood flow, and vascular resistance) were omitted. Review articles, unpublished abstracts, theses, and dissertations were also excluded.

Screening
Literature search results were entered into Mendeley, which automatically removed duplicates, then exported to Rayyan (i.e. online systematic review software). Two authors (DMS and AB) independently screened titles and abstracts for suitability. The full text for studies of interest were retrieved and independently evaluated for suitability by the same two authors. Disagreements between authors' decisions were resolved via discussion and consensus.

Risk of bias/quality assessment
Two authors (DMS and PMB) independently performed the assessment of risk of bias in the included studies using the Rosendal Scale [9]. This scale combines the PEDro scale [10], Jadad scoring system [11] and Delphi list [12]. This Rosendal scale was selected as the PEDro scale, Jadad scoring system and Delphi list have been extensively evaluated and validated. A Rosendal score of 60% is considered as excellent methodological quality [9]. Two checklist items were removed, including to whether the researchers were blinded as it was deemed inappropriate (i.e. due to safety reasons) and reporting of methods used to report adverse effects as the responses to acute hypoxia are inherently deemed adverse. An additional checklist item assessing whether treatment order was counterbalanced was included. No studies were excluded based on quality assessment results. Disagreements were resolved by discussion.
Simulator flight performance Unclear, but likely impaired flight performance Impaired flight performance following 6% (but not 8%) O 2 at~10 min; adverse subjective effects reported immediately after, such as light headedness, visual impairments and dizziness Effects are compared to a normoxic baseline (i.e. either immediately before the hypoxic intervention or during a separate trial), unless otherwise indicated.
Reduced SpO 2 and increased HR, but no effect for MAP, SBP and DBP SpO 2 normalised at 2 min and HR normalised at 6 min Steinback et al.
Increased HR, MAP and SBP, but no effect for DBP HR, MAP and SBP normalised at 10 min Stepanek et al.
EEG. Two studies measured EEG indices during recovery from hypoxia (Table 6). One study reported differences in EEG indices persisted for up to 4 hours with no difference between 21% and 100% oxygen recovery [5], whereas another study reported rapid Effects are compared to a normoxic baseline (i.e. either immediately before the hypoxic intervention or during a separate trial), unless otherwise indicated. *Comparisons were between conditions (not to baseline). Abbreviations: SpO 2 = peripheral blood haemoglobin oxygen saturation; HR = heart rate; HRV = heart rate variability; SDNN = standard deviation of RR intervals; rMSSD = root mean square of successive differences between normal heartbeats; LF = low-frequency power; HF = high-frequency power; MAP = mean arterial pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure.

State and limitations of evidence
The purpose of this systematic review was to consolidate the available evidence on the recovery of cognitive and basic physiological responses following an acute hypoxic exposure. This was to improve our understanding of how hypoxia could impair performance and compromise safety despite returning to normoxic (or hyperoxic) air breathing. Currently, there are insufficient published articles to accurately quantify post-hypoxia recovery profiles of cognitive and physiological indices, and their influential factors, which prevented meta-analysing the data and restricted this article to a systematic review. Some studies also employed methodologies that made it difficult to extract true recovery durations and, therefore, the time point for full recovery could not be determined. This was often due to articles not reporting time course profiles (i.e. repeated measures) and only reporting a single value that represented a range of time. The majority of research (19 studies) included men and women to allow findings to be applicable to both sexes; however, there was still a tendency to favour males. Study quality was moderate (average Rosendal score of 58 ± 15) and methodological differences made it difficult to compare between studies. Nevertheless, there is sufficient evidence supporting the presence of a 'hypoxia hangover' and to help to inform post-hypoxia restrictions.

Recovery of cognitive functions
Hypoxia exponentially degrades cognitive functions with increasing hypoxaemia until loss-ofconsciousness [4]. During hypoxia, there is preferential blood flow to posterior regions of the brain that are essential for regulating vital functions (e.g. breathing) [41] but are not highly involved in complex cognitive functions. Therefore, the anterior regions are more at risk of reduced oxygen delivery and, since they are involved in higher order and more complex cognitive processes, are easily degraded by hypoxia. This may be exacerbated by increased oxygen requirement of active brain regions and higher neuronal sensitivity to oxygen deprivation. In the present review, studies included a range of simple and complex cognitive tasks, and since some of these were not sensitive to the effects of hypoxia, they were unable to provide insight into the recovery period. Nonetheless, there appears to be persistent cognitive impairments for some standardised cognitive tasks (or domains) and more complex simulated flight performance tasks. The most informative study designs used repeated measures of simple tasks that have a short temporal resolution, such as reaction speed and attention (refer to Table 2). Initially, Phillips et al. (2009) reported choice reaction time was slower 10 min into recovery, with some Reduced MMN mean amplitude; no effect for MMN peak latency; increased P3a mean amplitude; no effect for P3a peak latency MMN mean amplitude normalised at 120 min (reduced at 0, 20 and 60 min); shorter MMN peak latencies normalised at 240 min (reduced at 20, 60, 120 and 180 min); P3a mean amplitude normalised immediately for 21% and 100% O 2 with no differences between 21% and 100% O 2 Malle et al.
Overall, no effect for EEG spectral power for all groups; however, SEF95 increased *Transient increase in slow-wave activity for both groups, including increased delta wave activity (first 16 sec, both groups) and theta wave activity (first 32 sec in 100% O 2 ); SEF95 transiently increased in 21% O 2 and decreased in 100% O 2 , with SEF95 lower in 100% compared with 21% O 2 during first 32 sec and from 64-80 Effects are compared to a normoxic baseline (i.e. either immediately before the hypoxic intervention or during a separate trial), unless otherwise indicated. participants exhibiting a slower reaction time compared to hypoxia [21]. The same researchers later demonstrated simple and choice reaction speed were slower after 1 and 2 hours into recovery, and normalised at 24 hours [20]; however, there were no measures between 2 and 24 hours, with full recovery likely occurring earlier. More recently, Blacker & McHail (2021) reported vigilant attention (i.e. mean reaction time using a 10 min psychomotor vigilance task) was reduced 20 min into recovery and normalised after 1 hour, with no differences between breathing 21% or 100% oxygen during recovery [5]. This was similar to an earlier study that reported total response time for simple and choice reaction time tasks normalising by 60 min [17]. These observations suggest that performance of both simple reaction time and more demanding vigilance tasks can be impaired in the hours following a hypoxic exposure. Performance of complex tasks were less informative as these are more difficult to measure. Since they typically take longer to assess, repeated measures are also difficult to ascertain. Similarly, studies reporting cognitive function for a single timepoint or range of time proximal to the cessation of hypoxia did not provide much insight into cognitive recovery profiles. Nevertheless, auditory serial addition task performance (a measure of attention and working memory) normalised at 90 sec [19], and task time and errors for serial number reading using the King-Devick test normalised at 5 min [25], suggesting rapid recovery. There may also be differences in sensory processing following hypoxia. For example, auditory monitoring tasks may recover at a slower rate compared to visual monitoring, memory and mathematical processing [13]. Future studies should aim to corroborate these findings and discern if there is a difference in post-hypoxia recovery profiles between simple and complex cognitive tasks, and how these are influenced by the hypoxic dose and recovery procedures.
Flight performance tasks are more reflective of the real-world implications posed by posthypoxia cognitive impairments. Robinson et al. (2018) assessed simulated flight performance in non-pilots concurrently with a time-estimation task during successive hypoxic exposures, but only comparisons between different recovery modalities were possible. Following hypoxic exposure (i.e. normobaric 6.5% oxygen for 5 min), there were no differences in flight and timeestimation task performance between 21% and 13.1% oxygen breathing after 35 min [22]. However, flight performance errors and time-estimation task lapses during recovery with 13.1% oxygen were higher when preceded by hypoxia compared with normoxia, suggesting there was an additive effect from the prior hypoxic exposure [22]. Further, Varis et al. (2019Varis et al. ( & 2022 assessed simulated flight performance during a return-to-base landing following an inflight hypoxic emergency on trained Hawk fighter pilots in two studies and reported impairments persisted for 10 min following exposure to 6% oxygen, alongside impaired situational awareness and adverse subjective feelings such as light headedness, visual impairments and dizziness [6,28]. Some participants also reported incidents when driving home following testing [6].

Recovery of physiological and neurophysiological status
Hypoxia elicits an integrated physiological response that stems primarily from peripheral chemoreceptors sensing hypoxaemia [42]. This chemoreflex is initiated from receptors predominantly located in the carotid body, which increase activity via the carotid sinus nerve that projects to the lower brainstem and nucleus tractus solitarius. This increases ventilation and autonomic sympathetic activity to raise HR and BP, and redistribute blood flow to critical tissues where vasodilation occurs, such as the brain [43]. The subsequent baroreflex initiates a vagal response and there seems to be a baroreflex resetting to shift baroreceptor activity to a higher threshold that allows for sustained and increased sympathetic innervation [36]. In severe hypoxia, compensatory responses are insufficient to maintain brain tissue oxygenation [44], which results in widespread slowing of EEG indices [19]. During normoxic recovery, HR and SpO 2 recover within seconds and only marginally faster when breathing 100% oxygen (refer to Table 3). This withdraws the primary chemoreceptor stimulus, yet some physiological perturbations persist.
Autonomic nervous system activity can be inferred using cardiac indices, such as HRV. During hypoxia, HRV indices tend to decline, including SDNN, rMSSD and LF and HF spectral domains (refer to Table 3), indicating greater sympathetic innervation and parasympathetic withdrawal; however, these seem to normalise within 3-20 min [14,15,19,23]. Sex and susceptibility to hypoxia also appear to influence the HRV response. For example, Botek et al. (2015) reported greater vagal withdrawal (i.e. lower HF spectral domain) during hypoxia and at 7 min into recovery in participants exhibiting a lower SpO 2 [14]. The same researchers later reported males had a relatively higher sympathetic response to hypoxia exposure compared with females (i.e. higher natural logarithm of SDNN/rMSSD and LF spectral domain), but differences did not persist at 7 min into recovery [15]. Therefore, HRV indices suggest the increase in sympathetic activity during hypoxia normalises minutes into recovery.
Increased sympathetic activity may, in fact, persist for longer than indicated by HRV indices. For example, several included articles also reported increased MSNA for at least 15-20 min into recovery [26,33,35,36,38]. Although MNSA was not included in this review due to it being a difficult measure to ascertain, it provides a direct measure of sympathetic activity and highlights that increased sympathetic activity during hypoxic recovery may not be fully captured by HRV. The reasons for this are uncertain and despite elevated post-hypoxia MNSA being reduced by periods of hyperoxic breathing to suggest reduced chemoreflex activity [35], the rapid normalisation of SpO 2 , end-tidal gases and VE indicates chemosensitivity is unlikely underpinning persistent elevated MSNA. Rather, increased MSNA is more likely due to other reasons, such as long-term potentiation of post-ganglionic nerves [35].
The cardiovascular response to hypoxia increases BP, particularly SBP, which appears to normalise within 5-20 min in most, but not all, studies (refer to Table 3). Increased BP initiates the baroreflex to increase vagal activation and during hypoxia there is an attenuated cardiac baroreflex to allow for vagal adaptation. For example, Roche et al. (2002) demonstrated the increased hypoxic sympathetic excitation can be followed by an upregulated parasympathetic drive stemming from overactivity of the baroreflex to cause relative bradycardia during recovery [23]. This reduction in post-hypoxia HR was also shown by Botek et al. (2015Botek et al. ( & 2018 [14,15]. The interaction of arterial carbon dioxide and hypoxia may also alter baroreceptor resetting, with poikilocapnic hypoxia potentially having less influence on baroreceptor resetting compared to isocapnic hypoxia [45]. These effects highlight a complex interplay of chemoreflex and baroreflex regulation during hypoxia and recovery. Brain tissue oxygenation (e.g. rSO 2 ) is a more informative measure than peripheral indices (e.g. SpO 2 ) of cognitive function [44]. However, studies measuring post-hypoxia rSO 2 using near-infrared spectroscopy (fNIRS) report conflicting findings. Phillips et al. (2009Phillips et al. ( & 2019 demonstrated rSO 2 remained reduced at 10 min [21] and 2 hours [20], and normalised by 24 hours into recovery [20]. These perturbations in rSO 2 mirrored performance impairments for SRT and CRT tasks [20,21]. Nonetheless, considering no measures were taken between 2 and 24 hours, rSO 2 probably normalised before 24 hours and, as these studies were not adequately controlled, the authors described the findings as preliminary. In comparison, Steinback et al. (2012) and Uchida et al. (2020) reported rSO 2 normalised 10-16 min into post-hypoxia recovery [27,39]. These differences are difficult to explain but are likely due to methodological differences in hypoxic and recovery interventions, and fNIRS measurement techniques, which may not necessarily accurately reflect brain tissue oxygenation [46]. Further, measures of frontal/prefrontal cortex oxygenation represents a tissue average and may not be sensitive to regional differences that can occur during hypoxia.
The ventilatory increase during hypoxia peaks after 5 min then declines over 20-30 min to a steady-state above pre-hypoxic levels [26]. This hyperventilation can cause hypocapnia if carbon dioxide is not administered within the breathing gas (i.e. poikilocapnic hypoxia), which may be an important physiological determinant in studies measuring flight performance during hypoxic recovery [28]. Ventilation typically normalised within 15 min following cessation of hypoxia (refer to Table 4) and, in some studies, this included an initial transient undershoot to below pre-hypoxic levels after returning to normoxia [40] and hyperoxia (compared to hyperoxic baseline) [16]. The ventilatory response to repeated hypoxic exposures may also be attenuated [31], which suggests central chemosensitivity is reduced, which could increase susceptibility to hypoxia by exacerbating hypoxaemia.
EEG measures provide insight into brain signalling activity. Malle et al. (2016) measured EEG waveforms whilst performing a demanding cognitive task (i.e. PASAT) and showed an increase in SEF95 during hypoxia (i.e. the frequency below which 95% of total EEG power was contained), suggesting an increase in fast-wave activity [19]. However, recovery with 100% oxygen breathing generated a robust EEG slowing for~30 sec (i.e. increase in theta activity and decrease in SEF95) [19], suggesting hyperoxia may elicit an initial harmful effect on the brain. Whereas, Blacker & McHail (2021) measured passive elicited event-related potentials that assess auditory processing, and demonstrated a continued decline in mismatch negativity (MMN) amplitude during post-hypoxia recovery, which normalised after 120 min, and a delayed response MMN peak latency, with shorter latencies that normalised after 240 min [5]. Whereas, P3a, a measure of attention, normalised immediately during recovery, and 100% compared with 21% oxygen breathing had no effect on recovery of EEG indices [5]. Therefore, pre-conscious auditory processing may require up to 2 hours to recover following a hypoxic exposure, which could be connected with the persistent impairment in auditory monitoring previously reported [13].

Perspectives and conclusion
Understanding recovery from hypoxia and its practical implications is critical for various populations. Current research suggests there may be lagging effects for the recovery of some cognitive and physiological indices, but temporal profiles are unclear. Generally, most research has focussed on measuring responses to hypoxia rather than during recovery following return to normoxic and/or hyperoxic breathing. The effects of hypoxia have largely been established and although there is a better need to understand how these affect behaviour and decision making within various real-world situations, further research also needs to consider the post hypoxic period. Impaired cognitive functions can compromise performance and safety, and there is emerging evidence to suggest complex real-world skills, such as piloting an aircraft, are impaired during the immediate minutes following a hypoxic exposure. Thus, if there is the assumption that recovery is rapid due to SpO 2 normalising within seconds-to-minutes, then individuals are likely to expose themselves to unnecessary risk during the post-hypoxia period that could result in serious or fatal incidents. This could occur following numerous situations, such as an inflight decompression at high-altitude, failure of oxygen supply systems to provide sufficient oxygen, hypoxia recognition training (i.e. standard military aircrew training), or after hypoxia research studies. However, the duration of potential impairments and the recovery profiles are unclear.
The mediating effects of the hypoxic dose and level of oxygen supplied during recovery is also uncertain. It seems plausible that the longer and more severe a hypoxic exposure, the longer the recovery period. However, whether interactions of F I O 2 (and/or barometric pressure) and duration that elicit similar hypoxic doses cause different recovery profiles should also be assessed. For example, studies within this review included prolonged moderate-hypoxia (e.g. 18,000 ft [5,486 m] equivalent or~10-11% oxygen) and short severe-hypoxia (e.g.~25,000 ft [7,620 m] equivalent or~7-8% oxygen) interventions, but it is unclear which elicits greater cognitive and physiological effects during the post-hypoxic recovery. With poikilocapnic hypoxia, there is also an increased risk of hypocapnia resulting from hyperventilation, which causes cerebral hypoperfusion to exacerbate the effects of hypoxia. Therefore, the mediating effect of adding carbon dioxide to the recovery gas also needs to be examined.
Hyperoxic breathing is currently a focal area of research, particularly in military aviation, and appears to have a beneficial effect on aspects of cognition [47]. Nonetheless, the use of 100% oxygen for recovery from hypoxia did not demonstrate a beneficial effect compared to normoxia. Rather, 100% compared with 21% oxygen breathing during recovery seemed to cause an EEG slowing and impaired cognitive performance during the initial seconds following hypoxia [19], but this was not reported for all studies [5]. This suggests hyperoxic recovery may be harmful, which has previously been eluded to in the military aviation context [4], yet remains standard practice. There may also be a paradoxical effect whereby hyperoxic or nomoxic breathing post-hypoxia elicits a transient worsening of cognitive functions and symptoms, termed the 'oxygen paradox' [48]. This is potentially due to a transient vasoconstrictive effect of hyperoxia that reduces cerebral perfusion and a drop in arterial blood pressure [49], thus exacerbating tissue hypoxia. However, to the authors' knowledge, there is no published literature demonstrating the effects of hyperoxia compared with normoxia on post-hypoxia cerebral perfusion and tissue oxygenation. In fact, there is scant research investigating the oxygen paradox, including cognitive, physiological and perceptive responses.
Whether hypoxia is induced by a reduction in barometric pressure or F I O 2 is critical to manage the risk of decompression sickness (DCS). Ascending above 18,000 ft (5,485 m), which is approximately half the atmospheric pressure at sea-level, is associated with an increased risk of venous gas emboli and DCS [50]. Although we did not include DCS risk within our review, this is an important consideration in the aviation context and pose a greater risk than hypoxia alone.
In summary, this systematic review suggests there is a need for post-hypoxia restrictions to minimise the risk of potential incidents and accidents due to lagging cognitive and physiological effects. As such, current evidence supports the presence of a 'hypoxia hangover' but the severity and duration of impairments are difficult to quantify and likely depend on several factors. Future research should aim to systematically assess a range of cognitive and physiological responses that persist into recovery following a hypoxic exposure, and the influence of different conditions (e.g. hypoxic dose and recovery procedures). This review suggests that recovery of SpO 2 and HR may only indicate partial recovery, and normalisation of other physiological indices can require to up to~2-4 hours to return to levels before the hypoxic exposure. It therefore seems appropriate that safety measures are implemented following acute hypoxic exposures to mitigate the risks imposed by persistent cognitive impairments and physiological perturbations.
Supporting information S1 Table. Methodological quality assessment summary.